Project Summary The vast heterogeneity of genetic and epigenetic features both among samples from any cancer type and within individual tumors has been documented with increasing resolution. Of note, intratumoral heterogeneity, which fuels clonal evolution and generates treatment resistance, has been identified as the foremost obstacle to lasting cure. This is true of chronic lymphocytic leukemia (CLL), an initially indolent malignancy of mature B cells which inevitably becomes more aggressive over time, and whose clinical course is highly variable across individuals. Despite the recent approval of highly potent drugs (i.e. ibrutinib, idelalisib) that target key CLL pathways, drug resistance?sometimes associated with highly aggressive relapse while on treatment?has been reported. The challenges presented by this disease heterogeneity mandate large-scale interdisciplinary approaches to link genomic features with cellular behavior so that effective personalized treatments can be devised. Our hypothesis is that CLL has heterogeneous yet coherent genomic alterations leading to distinct phenotypic behaviors, subject to evolutionary selective pressures, which impact individual disease trajectories. The members of the proposed Program have a successful track record of collaborating together to make landmark contributions to our understanding of CLL. Despite our growing knowledge about CLL and the expanding armamentarium of effective therapeutics targeting it, the next quantum leap in our understanding of this disease will require network-level integration across data layers in well-powered series to comprehensively map the circuitry of CLL (Projects 1, 2), and systematic approaches to evaluate the impact of genomic alterations on prognosis and response to therapy (Projects 2, 3). Certainly, conventional approaches to functionally study genetic lesions of CLL have been limited by the lack of faithful cell lines and mouse models and by the widely acknowledged difficulties in genetically manipulating primary CLL cells. Through major innovations in approaches to dissect CLL, spearheaded by each Project Leader and ranging from computational to functional genetic and non-genetic based readouts in primary human B cells, we are well- poised to synergize together to address clinically relevant questions in CLL. These initiatives are strongly supported by the joint expertise of the Core Leaders and are expected to inform us on the rational design of the next generation of personalized and curative therapies for CLL.